Abstract Recent studies have suggested an increased risk for atherosclerosis in patients with Helicobacter pylori (H. pylori) infection. However, the mechanism(s) for increased risk for atherosclerosis with H. pylori infection is currently unknown. It is well known that endothelial dysfunction plays a critical role in the development of atherosclerosis and related cardiovascular diseases. The preliminary data for the project have shown that H. pylori infection significantly impairs endothelium-dependent vasodilation in both patients and C57BL/6 mice. Eradication of H. pylori infection in patients and mice significantly improves endothelium-dependent vascular relaxation. Human endothelial cells cultured with serum exosomes from patients with H. pylori infection exhibited significant dysfunction with decreased migration, proliferation, and tube formation in vitro. Exosomes derived from conditioned media of human gastric epithelial cells cultured with H. pylori bacteria containing H. pylori virulent factor cytotoxin-associated gene A (CagA) also significantly decreased endothelial functions similar to serum exosomes. The present project is proposed to test the hypothesis that H. pylori infection impairs endothelial function through exosome-mediated mechanism. The specific aims are: 1) to investigate the effect of H. pylori infection on endothelial function; and 2) to define the role of exosomes in mediating the effect of H. pylori infection on endothelial function. Since the vast majority of patients with H. pylori infection are infected with the bacteria containing the virulence factor CagA, the mice (C57BL/6 mice, both male and female) will be infected with CagA+ H. pylori for the proposed experiments. To determine the effect of CagA protein on endothelial function, CagA- (negative) H. pylori will also be used to repeat the in vitro and in vivo studies for comparison. Endothelial function will be determined in the mice infected with either CagA+ or CagA- H. pylori with PBS as well as inactivated H. pylori as controls. To evaluate the role of exosomes in mediating the effect of H. pylori infection on endothelial function in vivo, the animals will be treated with GW4869 to decrease the release of exosomes from cells. If the hypothesis is true, it is expected that endothelial function will be significantly decreased in the mice infected with either CagA+ or CagA- H. pylori (more so with CagA+ H. pylori if CagA is important to H. pylori infection-induced endothelial dysfunction). Inhibition of exosomes secretion with GW4869 is anticipated to effectively restore endothelial function in mice with H. pylori infection. The data from the proposed study will provide novel insights into the mechanisms for the development of vascular dysfunction in the patients with H. pylori infection, and help explore new and effective strategies to preventing and treating cardiovascular diseases especially atherosclerosis associated with H. pylori infection.